Synthetic Antidiarrheal Agents
Journal of Medicinal Chemistry, 1973, Vol. 16, No. I
49
Synthetic Antidiarrheal Agents. 1 . An Approach to the Separation of Antidiarrheal Activity from Narcotic Analgesic Activity Donald E. Butler,” Robert F. Meyer, Susan M. Alexander, Paul Bass, and John A. Kennedy Chemistry Department, Research and Development Division, Parke, Davis and Company, Ann Arbor, Michigan 481 06. Received May 23, I972
A series of 1-(disubstituted amino)-3-(dialkylaminoalkyl)-3-phenyloxindoleswas found in which analgesic
or dependence liability as measured by the Straub tail effect in mice could be separated from a constipating effect. The best separation of effects was found in the 1-[(substituted benzyl)methylamino]-3-(dialkylaminoalkyl)-3-phenyloxindoles.Of a number of substitutions on the benzyl group, an o-chloro resulted in consistent separation of the biological activities. The nmr spectra of 1-[( 1-substituted benzyl)methylamino]3-phenyloxindoles demonstrate restricted rotation around the N-N bond. In certain diseases, diarrhea can be the cause of a high degree of morbidity and even mortality.’ The narcotic analgesics remain the drugs of choice for the treatment of diarrhea and dysentery. This group of drugs has the disadvantage of possessing narcotic and dependence liabilities. In man the parallelism of narcotic and constipating properties in any series of analgesics has not been systematically explored. It is apparent that morphine and methadone which have similar narcotic properties do not appear t o have similar constipating effects’ and morphine and codeine do not possess the same degree of addiction l i a b i l i t ~ . ~ Clinically, increased colonic contractile activity is associated with the constipating effect. The ideal constipating drug would increase colonic circular muscle activity without stimulation of the longitudinal muscle and without other pharmacological actions. Narcotic analgesics have the general property of increasing intestinal activity in v i ~ o but ~ - ~ with many other undesirable effects for a constipating drug. Janssen and Jageneau” have previously noted the poor correlation between “analgesic” and “constipating” activity in a series of analgesically active meperidine derivatives. Evaluation of a series of chemicals led to the introduction of diphenoxylate into the therapeutic regimen of diarrhea control.””’ This agent possesses morphine-like as well as anticholinergic properties, both of which may be responsible for its antidiarrheal action. Diphenoxylate, because of its narcotic properties, is capable of supporting mor hine physical dependence in man12 and the monkey ;“overdose in children has led to symptoms and fatalities that were characteristic of the narcotics, e.g., respiratory depression and narcosis (reversed by Nalorphine).14j15 We considered that a chemical could be found that would have antidiarrheal activity without dependence liability or other significant side effects. Janssen, Jageneau, and Huygens” had used the mouse hot plate16 and the charcoal meal in the development of diphenoxylate. Since morphinedependent monkeys can be supported by diphenoxylate, we felt that a different approach was needed. Shemano and Wendel” had compared the pharmacological profile of Nallylnormorphine (Nalorphine), a nonaddicting compound, with that of morphine and had noted that Nalorphine lacks certain central stimulatory effects of morphine, namely, excitation of the cat and a Straub tail in mice. A general relationship has been found between the cat excitatory effect and human addiction liability of morphinelike drugs, but the correlation was not clear-cut .‘l We decided to use the Straub tail effect as one of our primary tests because of its simplicity and because Juu122had shown that codeine was approximately one-tenth as effective as morphine in causing the Straub tail effect and, as noted by
Fraser and coworker^,^ “although codeine accounts for at least 80% of the natural opiates sold on prescription. . ., the incidence of addiction to codeine is much less than that to morphine.” Our synthetic efforts have been directed toward maximizing the antidiarrheal action and eliminating or minimizing the Straub tail effect, the premise being that a compound which possesses a high degree of antidiarrheal activity with little or no Straub tail effect in mice will possess little or no addiction liability in man. Since our work began, a study by Aceto, McKean, and has shown the Straub tail test to be useful for studying structure-activity relations among opiates and opiate antagonists. In Vivo Biological Activity. Antidiarrheal. The test compounds were evaluated for oral antidiarrheal activity in the rat using the method of Kennedy, Wiley, and Bass.24 Briefly, the method involved dosing the animals PO and collecting the fecal output over an 8-hr period (4 P.M.-12 midnight). A total of 24 rats per dose was used along with a concomitant control group. The ED50 values were confirmed by repeating the test using doses that bracketed the original result. If an EDs0 was not obtained, the results were expressed as the per cent reduction of fecal output at the dose used. Straub Tail and/or Provisional Acute Toxicity. The test compounds were injected intraperitoneally to groups of five mice at doses of 250, 125,63, . . ., mg/kg until no drug effect was observed. The compounds were either dissolved in dilute HCl or propylene glycol. The animals were observed by highly trained personnel for 15-30 min. Surviving animals were held for 24 hr to establish a provisional acute toxicity. Compounds with a good separation of activity were tested in an anesthetized dog preparation against the effects of acetylcholine to check for anticholinergic activity. Chemistry. A series of l-(dialkylamino)-3-(dialkylaminoalkyl)-3-phenyloxindoleshad demonstrated analgesic activThis early group of compounds showed a wide divergence between antidiarrheal activity, Straub tail effect, and analgesic potency, although the latter two were closely parallel. The preparation of these compounds followed the scheme outlined in Scheme I. The first step is a modification of the original synthesis by Meyer.ty26When the unsymmetrical hydrazine was commercially available, it was used in excess. In general, an unsymmetrically substituted hydrazine was added to an ?Our thanks t o Mr. H . D. Troutman who suggested the use o f 4ethylmorpholine as an acid acceptor as a means of conserving the 1,l-disubstituted hydrazines (triethylamine was inferior).
50
Butler, et al.
Journal of Medicinal Chemistry, 19 73, Vol. 16, No. 1
gg
G
3:
i
z u-
P
z
r r
-
-
r
c
E i
3 C
a
Y i4 T
E C
c-
: C
b
-
Synthetic Antidiarrheal Agents
Journal of Medicinal Chemistry, I 9 73, Vol. 16, NO. 1
.d
Y
h
6
5I
Butler, et al.
Journal of Medicinal Chemistry, 1973, Vol. 16, No. 1
52
Table IIa
No.
R3
MP or bp (mm), “C
R4
Purification solventc
Yield, %
Formula
Analyses
9Bb 90-91 75 CH3 CH3 C 72 99 120.5-122.5 A (CHz)s 134-1 36.5 67 A (CHz)zO(CHz )z 100 114-116 32 101 A 102 B 91-93 75 B 126.5-129 47 103 69-7 1 A 104 61 85-87 A 105 68 8 3-85 71 A 106 88-90 B 68 107 47 86-88 B 108 70 100-102 A 109 71 B 87-91 110 D 52 121-122 111 B 69 80-82 112 52 84-86 B 113 213-215 (1.3) 66 114 180-185 (0.15) 60 115 B 102-103.5 68 116 50 185-195 (0.30) 117 B 74 118-120 118 E 31 114-115.5 119 61 105-108 E 120 B 48 122-126 121 79 108-1 10 F 122 78-80 B 67 123 71 B 112-1 1 3 124 F 97-99 48 125 E 117-120 54 126 B 118-120 63 127 F 96-99 56 128 F 124-127 65 129 E 90-9 3 52 130 A 110-1 12 52 131 97-99 66 A 132 70 A 110-1 1 2 133 A 123-125 65 134 41 A 87-92 135 I7 F 81.5-83.5 136 57 B 97-100 137 50 A 99-101 138 116.5-1 17.5 50 A 139 aThese compounds possessed no Straub tail or antidiarrheal activity. %ee ref 26. CA, 2-propanol; B, ethanol; C, cyclohexane; D, 2propanol-methanol; E, methanol; F, benzene-petroleum ether. dC: calcd, 77.07; found, 77.82. N: calcd, 7.82; found, 6.70. Scheme I
n O 2 Et , ,N
1 . NaH
m
O 2 . X(CHz)nN,-/ R Il
q
o N N
R3/ ‘R, 98- 139
2 . X(CH,),N\
RZ KZ
.
or a . X(CH,),X /,R, Rl aand n d bb.. HHN N’ . R,
’’
623
(CHZ)nN,
I
R3NN‘R4 1-97
/Rl R2
EtzO (THF) solution of 1 equiv of a-chlorodiphenylacetyl chloridez7followedby the addition of 2 equiv of 4-ethylmorpholine to yield the 1-dialkylamino-3-phenyloxindoles. Physical data of these new compounds are in Table 11. Treatment of the oxindoles with 1 equiv of NaH in THFPhCH3 followed by the addition of a dialkylaminoalkyl halide resulted in the final products. In some cases, an a,wdihaloalkane was used and the resulting I-(dialky1amino)-3(~-haloalkyl)-3-phenyloxindole was allowed to react with the appropriate amine. The title compounds along with their biological activities are in Table I. Table 111 contains 3-(w-haloalkyl)oxindoles, oxindoles that are substituted on the aromatic rings, and some miscellaneous derivatives. The active compounds have been disclosed in a U. S. Patent ,28 Structure-Activity Relationship. A significant separation of antidiarrheal activity from the Straub tail effect was obtained when the 1 substituent was an alkylaralkylamino
Journal of Medicinal Chemistry, 1973, Vol. 16, No. 1
Synthetic Antidiarrheal Agents
53
Table III'
Z N
'R,
R,' No.
R.
R"
W
Z
Mp or bp (mm), Purification OC solventb Yield, % Empirical formula
Analyses
c1 173-175 H CH, C,,H,,CI,N,O C, H A 65 CH,O 120-121 C18H20N203 C, H, N A 50 CH, H 141d 88-90 H (CH,),Br A 71 C,,H,9BrN,0 C, H, N 142 CH, 101-103 H C,,H,,BrN,O C, H A 70 (CH,),Br 143 CH, 144 C,H,CH, (CH,),Br H Oile C24H23BrN20 145 C,H,CH, (CH,),Br H 0ile C25H25BrN20 146 C,H,CH, (CH;),Br H 0ile C26H27BrN20 B 50 (CH,),Br H 116.5-120 147 C,,H,,BrClN,O C, H 2-C1C,H4CH, (CII, ),Br H 104-1 06 A 63 148 C,,H,,BrN,OS C, H, N 2CH,SC,H,CH, 149 CH, (CH,),N(C,H,), C1 190-1 9 3 A 55 C,,H,,Cl,N,O~HCl C, H C1 129.5-131 C,,H,,Cl,N,O C, H (CH,),N(CH,), A 60 150 CH, C1 101-1 0 4 (CH,),N(CH,), C,,H,,Cl,N,O C, H G 50 151 CH, A 50 H 193-196 (CH,),N(CH,), C,,H,,N,O~HCl C, H H 152f 232-237 E 54 (CH,),N(CH,), H C,oH,,N,O~HC1 C, H H 15g 185-195 (0.15) CH,O (CH,),N(C,H,), C24H33N303 C, H, N 75 154 CH, aThese compounds possessed n o Straub tail or antidiarrheal activity. *See footnote b, Table 11, G, heptane. CBis(4-chlorophenyl)acetic acid was converted t o the acid chloride using SOCl, and treated with Br, and hu, and the resulting a-bromobis(4-chloropheny1)acetyl chloride was treated with an excess of 1,ldimethylhydrazine. dp.Anisilic acid was treated with 1 equiv of PCl, in the manner of Stevens and Frenchz7 and the crude product was allowed t o react with an excess of 1,ldimethylhydrazine. eThese oils were used crude in the amination reaction. fThis compound was prepared by catalytic (20% Pd/C) hydrogenation of compound no. 16 in MeOH. gThis was prepared as in f o o t n o t e f o n compound no. 17.
140'
CH, CH, CH, CH, CH, CH, CH, CH, CH, CH, CH, CH, CH, CH, CH,
group. The separation was enhanced when the aralkyl moiety was a benzyl group with an o-chloro, bromo, methoxy, alkylthio, or trifluoromethyl substituent (see compounds no. 22,25,33,34,40,42,44,45). This was also true of a number of disubstituted analogs (see compounds no. 68-70,78). A dialkylaminoalkyl substituent on the three position was essential for any biological activity. Separation of the amino from the three position by two carbons gave the most potent compounds. Most other changes resulted in the reduction or elimination of either or both biological actions. These are represented in Table I with a minimum of examples. Some inactive derivatives with substituents on the 3-aryl group and aryl portion of the oxindole are included in Table 111. The active compounds did not antagonize the blood pressure effects of acetylcholine in an anesthetized dog preparation.
Experimental Section$ General Procedure for the Preparation of the Oxindoles. T o a stirred solution of 265.15 g (1.0 mol) of a-chlorodiphenylacetyl chloridez7 in 1 1. of THF was added a solution of 1 equiv of a 1 , l disubstituted hydrazine in 100 ml of THF. The mixture was refluxed 1 hr and cooled under N, t o 15". With stirring, 230.4 g (2.0 mol) of 4ethylmorpholine was added and the mixture was refluxed 90 min. The mixture was cooled to 0" under N, and the 4ethylmorpholine hydrochloride was removed by filtration. The filtrate was concentrated on a rotary evaporator and diluted with an equal volume of i-PrOH. In the majority of cases, the oxindole crystallized and could be alkylated without further purification. If the product failed to crystallize, the i-PrOH was stripped from the oil. The oil was dissolved in Et,O o r PhCH, and washed with dilute NaOH. The organic layer was dried over anhydrous MgSO,, filtered, concen$The melting points were taken on a Thomas-Hoover melting point apparatus and are uncorrected. A Beckman IR-9 spectrophotometer was used t o determine the infrared spectra. The nuclear magnetic resonance spectra were obtained with a Varian A-60 spectrometer. Where analyses are indicated b y symbols of the elements, analytical results obtained were within +0.4% of t h e theoretical values.
trated, and redissolved in i-PrOH. A few of the oxindoles were distilled and used as oils. The amide ir band was found between 1680 and 1720 cm-'. The nmr spectra of the l-(benzylmethylamino)-3phenyloxindole type is complex because of restricted rotation around the N-N bond. The benzylic protons and the 3-H appear as a multiplet between 3.9 and 4.8 ppm depending upon the substituent on the aromatic ring. The N-methyl protons appear as an unequal doublet between 2.7 and 3.1 ppm. General Procedure for the Alkylation of the Oxindoles (Procedure A). This is a variation of the procedure of Zaugg and DeNet. 8 T o a heated (60-70') stirred solution of 0.1 mol of NaH in 150 ml of PhCH, and 25 ml of THF under a gentle stlearn of N, 8 was added 0.1 mol of oxindole (portionwise through a powder funnel). Then a solution of 0.1 mol of a dialkylaminoalkyl halide in 100 ml of PhCH, was added over a 15-min period. The mixture was refluxed 3-18 hr depending upon the reactivity of the halide. The mixture was cooled to 25" and 10 ml of H,O added. The product was extracted into dilute HCl. The acidic extracts were made strongly basic with NaOH and extracted with EtzO. The extracts were dried over anhydrous MgSO,, filtered, concentrated, and distilled or recrystallized. The C=O ir absorption was in the same range as in the unalkylated oxindoles. The alkylations with a,w-dihaloalkanes were carried o u t in the same manner or by addition of a twofold excess of the a,wdihaloalkane before the addition of the NaH. All of the l-(dialkylamino)-3-(w-haloz!kyl)-3-phenyloxindoles were contaminated with the product from the reaction of the anion with both halogens. This type of impurity was separated by the acid extraction step following amination. General Procedure for the Reaction of the l-(Dialkylamino)-3(w-haloakyl)-3-phenyloxindoleswith Amines (Procedure B). The halides were refluxed for 1 8 hr with an excess of a secondary amine. If the amine was low boiling, the two components were heated at 100" for 1 8 hr in a sealed pressure vessel. The isolation procedure was the same as that used for the alkylation reaction. The 1,l-disubstituted hydrazines were prepared by methods summarized el~ewhere.~'As reported by other^,^' many of these §DMF, THF, and DMSO have all been used successfully; however, up t o 30% of t h e alkylated product has been found in the water-polar solvent mixture b y concentration on the rotary evaporator and reextraction. The procedure described makes this unnecessary. The alkylation has also been carried out using NaOCH, in MeOH. The N, atmosphere is necessary because of the ease of oxidation at the 3 uosition of the oxindole in the uresence of base and air.
54
McLean, Swamy, Tomei, Triggle
Journal of Medicinal Chemistry, 1973, Vol. 16, No. 1
were difficult t o analyze as bases. They were used successfully in the oxindole synthesis after distillation and without further purification.
Acknowledgments. The authors wish to express their appreciation to Dr. L. M. Long, Dr. A. C. Bratton, Jr., and the late Dr. D. H. Kaump for encouragement in this investigation. We also thank Mr. C. E. Childs and associates for the microanalyses, Dr. J. M. Vandenbelt and associates for the spectral data, and Mr. W. M. Pearlman for the performance of many hydrogenations involved in the preparation of starting materials. We also thank Dr. D. A . McCarthy and associates for the Straub tail and anesthetized dog data. References (1) H. L. Dupont and R. B. Hornik, “Diarrheal diseases. Disease-aMonth,” Yearbook MedicalPublishers, Chicago, Ill., 1969. (2) L. S. Goodman and A. Gilman in “The Pharmacological Basis of Therapeutics,” 3rd ed, Macmillan. New York. N. Y . . 1965. p 271. H. F. Fraser, G. D. Van Horn, W. R. Martin, A. B. Wolbach, and H. Isbell, J. Pharmacol. Exp. Ther., 133, 371 (1961). A. M. Connell, Gut, 3, 342 (1962). H. Kruger, Physiol. Rev., 17, 618 (1937). J. Neely, Brit. J. Surg., 56, 925 (1969). P. Bass and J. N. Wiley, Amer. J. Physiol., 208, 908 (1965). P. Bass and J . N. Wiley, Amer. J. Dig. Dis., 10, 1 8 3 (1965). J. A. Rinaldo, Jr., E. A. Orinion, R. V. Simpelo, F. E. Check, and W. Beauregard, Gastroenterology, 6 0 , 4 3 8 (1971). P. A. J . Janssen and A. H. Jageneau,J. Pharm. Pharmacol.. 9, 381 (1957). P. A. J. Janssen, A. H. Jageneau, and J . Huygens, J. Med. Pharm. Chem.. 1, 299 (1959).
H. F. Fraser and H. Isbell, Bull. Narcotics, 13, 29 (1961); Chem. Abstr., 61, 3592 (1964). D. A. McCarthy, R. H. Burns, G. A. Deneau, and M. H. Seevers in “Committee on Drug Addiction and Narcotics,” Minutes of Nineteenth Meeting, Addendum 2. National Academy of Sciences, National Research Council, Washington, D. C., 1958. p 10. J. T. Harries and M. Rossiter, Lancet, 1, 150 (1969). W. Henderson and A. Psaila, ibid., 1, 307 (1969). F. Haffner, Deut. Med. Wochenschr., 55, 731 (1929). I. Shemano and H. Wendel, Toxicol. Appl. Pharmacol., 6, 334 (1964). W. Straub, Deut. Med. Wochenschr.. 37, 1462 (1911). W. J . R . Heinekamp, J. Pharmacol. Exp. Ther., 2, 107 (1922). D. L. J. Bilbey, H. Salem, and M. H. Grossman,Brit. J. Pharmacol., 1 5 , 5 4 0 (1960). H. Collumbine and T. S. Konop, Can J. Biochem. Physiol., 37, 1075 (1959). A. Juu1,Arch. Int. Pharmacodyn. Ther., 6 2 , 6 9 (1939). M. D. Aceto, D. B. McKean, and J . Pearl, Brit. J. Pharmacol., 36, 225 (1969). J. A. Kennedy, J. N. Wiley, and P. Bass, Arner. J Dig Dis., 17, 925 (1972). R. F. Mever t o Parke. Davis and Co.. U. S. Patent 3.314.954 , , (1967). R . F. Meyer, J. Org. Chem.. 30, 3451 (1965). C. L. Stevens and J . C. French, J. Amer. Chem. Soc.. 75, 657 ( 195 3). D. E. Butler t o Parke, Davis and Co., U. S. Patent 3,595,866 (1971). H. E. Zaugg and R. W. DeNet, J. Amer. Chem. Soc., 8 4 , 4 5 7 6 (19 62). D. E. Butler and S. M. Alexander, J. Med. Chem.. 14, 1052 (1971). H. Zimmer, L. F. Audrieth, M. Zimmer, and R. A. Rowe. J. Amer. Chem. Soc.. 77. 790 (1955).
Irreversible Adrenergic a-Receptor Antagonism by ( R)- and (S)-N-(2-Chloroethyl)-N-methyl-2-phenyl-2-hydroxyethylamine and Related Agents S . McLean, V. C. Swamy, D. Tomei, and D. J. Triggle” Department of Biochemical Pharmacology, School o f Pharmacy, State University of New York a t Buffalo, Buffalo. New York 14214. Received June 26, 1972
The synthesis of the title compounds is described from the corresponding mandelic acids. The compounds were significantly less effective than phenoxybenzamine as irreversible a-adrenergic receptor antagonists. The S isomer was more effective than the R isomer by a factor of 6. Interpretation of these differences is complicated by the finding that these agents, in common with many other 2-halogenoethylamines, appear to produce their actions through at least two different sites of reaction. The 2-halogenoethylamines have been extensively emmandelic acids, agents of impeccable stereochemical pediployed as irreversible adrenergic a-receptor antagonists,’?’ gree,* according to the sequence shown in Scheme I. although their activity is not confined to this receptor sysScheme 1 tem.’ Attempts to analyze the structure-activity relationC,H,CHOHCH,X C H CHCH,X ships of these agents in terms of postulated models of (1 norepinephrine binding at the a receptor3 suffer from a I OSiMe, number of disadvantages.’ In particular, the structural rela11 tionship of many of these agents, with the possible exception of the N,N-dimethy1-2-aryl-2-halogenoethylamine~,’~~~~ C,H,CHCH,N(CH,)CH,CH,OH I to norepinephrine seems rather obscure. Furthermore, we OSiMe, have recently shown that a major site of interaction of ir111 reversible adrenergic a-receptor antagonists is at a Ca” binding/mobilization site rather than the norepinephrine recogC,H,CHOHCH,N(CH,)CH,CH~CI nition ~ i t e . ~ > ~ HC1 It thus appeared of interest to investigate compounds that IV, (R )-(+) are structurally more closely related to norepinephrine. (SI-(-) Experimental Section Our initial investigations centered on N-(2-chloroethyl)-Nmethyl-2-hydroxy-2-phenylethylamine (IV) in its enantioMelting points were determined on a Thomas-Kofler hot stage meric forms. These were synthesized from optically active and are corrected. Analyses were performed by Dr. A. E. Bernhardt
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